Erythropoietin is a hypoxia inducible hormone required for survival, proliferation, and differentiation of erythroid progenitor cells. Expression of the erythropoietin receptor is not restricted to hematopoietic cells and exhibits a multi-tissue distribution that includes neural cells, vascular endothelium and muscle progenitor cells. The ability for erythropoietin to stimulate progenitor cell proliferation and prevent apoptosis is critical for maintenance of the erythroid lineage, but is also observed in neural and muscle progenitor cells. Mice lacking the erythropoietin receptor die in utero due to severe anemia. However, even prior to lack of erythroid cell production in the embryo proper, these mice exhibit increased apoptosis in brain as early as E10.5 and a reduction in the number of neural progenitor cells. Corresponding cultures of primary neural cells exhibit decrease neuron generation and increased sensitivity to reduced oxygen tension, and neurons do not survive after 24 hours at low oxygen tension. In contrast, hypoxia induces erythropoietin and erythropoietin receptor in wild type neuronal cells and erythropoietin enhances neuron survival at low oxygen tension. In vivo erythropoietin is neuroprotective in adult animal models for brain ischemia. Induction of erythropoietin and its receptor by hypoxia likely contributes to its neuroprotective activity and selective cell survival in the brain during hypoxic stress. Erythropoietin receptor expression in brain is not required for life and we created conditional knockout mice with selective erythropoietin receptor expression in hematopoietic tissue that allows survival to adulthood. Studies of neural cells from the rescue mice suggest that the protective effects associated with exogenous erythropoietin administration in response to ischemia/stress may reflect a protective role of endogenous erythropoietin activity in the brain to maintain neural cells in vivo. Erythropoietin can also stimulate proliferation and angiogenesis of endothelial cells that express erythropoietin receptors. Endothelial nitric oxide synthase produces nitric oxide, which maintains blood pressure homeostasis and blood flow. We found that erythropoietin receptors is inducible by erythropoietin in select primary human endothelial cells to a much greater extent at low oxygen tension than in room air. Increase of receptor expression results in an increase in erythropoietin response with induction of endothelial nitric oxide synthase as well as nitric oxide and cyclic guanosine monophosphate production. Stimulation of nitric oxide production was dose dependent on erythropoietin with a maximal induction at 5 units per microliter. These results suggest that low oxygen tension increases endothelial cell capacity to produce nitric oxide in response to erythropoietin by induction of both erythropoietin receptors and endothelial nitric oxide synthase. This effect of erythropoietin on vascular endothelium may counterbalance the hypertensive effects of increased hemoglobin-related nitric oxide destruction resulting from hypoxia-induced increased red cell mass.